Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23
- Author
- Yehudi Bloch (UGent) , Jan Félix (UGent) , Romain Merceron (UGent) , Mathias Provost (UGent) , Royan Alipour Symakani (UGent) , Robin De Backer (UGent) , Elisabeth Lambert (UGent) , Ahmadreza Mehdipour (UGent) and Savvas Savvides (UGent)
- Organization
- Project
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- HPC-UGent: the central High Performance Computing infrastructure of Ghent University
- Towards the structural and molecular basis of signaling assemblies mediated by the pruritogenic Interleukin-31.
- Towards the structural and molecular basis of pro-inflammatory signalling assemblies mediated by IL-23 and IL-12
- Abstract
- Cell-surface receptor complexes mediated by pro-inflammatory interleukin (IL)-12 and IL-23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12-receptor interaction interfaces, in contrast to IL-23-receptor complexes. Here we report structures of fully assembled mouse IL-12/human IL-23-receptor complexes comprising the complete extracellular segments of the cognate receptors determined by electron cryo-microscopy. The structures reveal key commonalities but also surprisingly diverse features. Most notably, whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their alpha-subunit as a hotspot to interact with the N-terminal Ig domain of their high-affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell membrane. Collectively, our findings will help to complete our understanding of cytokine-mediated assemblies of tall cytokine receptors and will enable a cytokine-specific interrogation of IL-12/IL-23 signaling in physiology and disease. Structures of complete extracellular receptor assemblies mediated by the pro-inflammatory cytokines IL-12 and IL-23 reveal key commonalities and diverse features, with only IL-12 juxtaposing receptor domains proximal to the cell membrane.
- Keywords
- PARTICLE CRYO-EM, MOLECULAR-DYNAMICS, HETERODIMERIC CYTOKINE, ORIENTATION, DISTINCT, SUBUNIT, REVEALS, SYSTEM
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01HS0JG3FYZ3FBWHXYP670TEFK
- MLA
- Bloch, Yehudi, et al. “Structures of Complete Extracellular Receptor Assemblies Mediated by IL-12 and IL-23.” NATURE STRUCTURAL & MOLECULAR BIOLOGY, vol. 31, no. 4, 2024, pp. 591–97, doi:10.1038/s41594-023-01190-6.
- APA
- Bloch, Y., Félix, J., Merceron, R., Provost, M., Alipour Symakani, R., De Backer, R., … Savvides, S. (2024). Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 31(4), 591–597. https://doi.org/10.1038/s41594-023-01190-6
- Chicago author-date
- Bloch, Yehudi, Jan Félix, Romain Merceron, Mathias Provost, Royan Alipour Symakani, Robin De Backer, Elisabeth Lambert, Ahmadreza Mehdipour, and Savvas Savvides. 2024. “Structures of Complete Extracellular Receptor Assemblies Mediated by IL-12 and IL-23.” NATURE STRUCTURAL & MOLECULAR BIOLOGY 31 (4): 591–97. https://doi.org/10.1038/s41594-023-01190-6.
- Chicago author-date (all authors)
- Bloch, Yehudi, Jan Félix, Romain Merceron, Mathias Provost, Royan Alipour Symakani, Robin De Backer, Elisabeth Lambert, Ahmadreza Mehdipour, and Savvas Savvides. 2024. “Structures of Complete Extracellular Receptor Assemblies Mediated by IL-12 and IL-23.” NATURE STRUCTURAL & MOLECULAR BIOLOGY 31 (4): 591–597. doi:10.1038/s41594-023-01190-6.
- Vancouver
- 1.Bloch Y, Félix J, Merceron R, Provost M, Alipour Symakani R, De Backer R, et al. Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23. NATURE STRUCTURAL & MOLECULAR BIOLOGY. 2024;31(4):591–7.
- IEEE
- [1]Y. Bloch et al., “Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23,” NATURE STRUCTURAL & MOLECULAR BIOLOGY, vol. 31, no. 4, pp. 591–597, 2024.
@article{01HS0JG3FYZ3FBWHXYP670TEFK,
abstract = {{Cell-surface receptor complexes mediated by pro-inflammatory interleukin (IL)-12 and IL-23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12-receptor interaction interfaces, in contrast to IL-23-receptor complexes. Here we report structures of fully assembled mouse IL-12/human IL-23-receptor complexes comprising the complete extracellular segments of the cognate receptors determined by electron cryo-microscopy. The structures reveal key commonalities but also surprisingly diverse features. Most notably, whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their alpha-subunit as a hotspot to interact with the N-terminal Ig domain of their high-affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell membrane. Collectively, our findings will help to complete our understanding of cytokine-mediated assemblies of tall cytokine receptors and will enable a cytokine-specific interrogation of IL-12/IL-23 signaling in physiology and disease.
Structures of complete extracellular receptor assemblies mediated by the pro-inflammatory cytokines IL-12 and IL-23 reveal key commonalities and diverse features, with only IL-12 juxtaposing receptor domains proximal to the cell membrane.}},
author = {{Bloch, Yehudi and Félix, Jan and Merceron, Romain and Provost, Mathias and Alipour Symakani, Royan and De Backer, Robin and Lambert, Elisabeth and Mehdipour, Ahmadreza and Savvides, Savvas}},
issn = {{1545-9993}},
journal = {{NATURE STRUCTURAL & MOLECULAR BIOLOGY}},
keywords = {{PARTICLE CRYO-EM,MOLECULAR-DYNAMICS,HETERODIMERIC CYTOKINE,ORIENTATION,DISTINCT,SUBUNIT,REVEALS,SYSTEM}},
language = {{eng}},
number = {{4}},
pages = {{591--597}},
title = {{Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23}},
url = {{http://doi.org/10.1038/s41594-023-01190-6}},
volume = {{31}},
year = {{2024}},
}
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